Epithelial-to-Mesenchymal Transition Drives Invasiveness of Breast Cancer Brain Metastases

SIMPLE SUMMARY: The prevalence of breast cancer brain metastasis has increased over the last decades, yet those patients are considered untreatable. Surgical removal of brain metastases is impeded by the presence of infiltrative tumor cells; however, the identity and behavior of those cells remain understudied. We demonstrate that cancer cells that invade the brain parenchyma are in a mesenchymal state and undergo EMT. We also demonstrate that removing those infiltrated tumor mesenchymal cells improves the efficacy of surgery and opens new avenues to better treat patients. ABSTRACT: (1) Background: an increasing number of breast cancer patients develop lethal brain metastases (BM). The complete removal of these tumors by surgery becomes complicated when cells infiltrate into the brain parenchyma. However, little is known about the nature of these invading cells in breast cancer brain metastasis (BCBM). (2) Methods: we use intravital microscopy through a cranial window to study the behavior of invading cells in a mouse model of BCBM. (3) Results: we demonstrate that BCBM cells that escape from the metastatic mass and infiltrate into brain parenchyma undergo epithelial-to-mesenchymal transition (EMT). Moreover, cells undergoing EMT revert to an epithelial state when growing tumor masses in the brain. Lastly, through multiplex immunohistochemistry, we confirm the presence of these infiltrative cells in EMT in patient samples. (4) Conclusions: together, our data identify the critical role of EMT in the invasive behavior of BCBM, which warrants further consideration to target those cells when treating BCBM.